Parkinson disease (PD) is a common neurodegenerative disorder involving the loss of midbrain dopaminergic (mDA) neurons in the substantia nigra, with diminished dopamine release in the striatum.1,2Rapid progress in human induced pluripotent stem cell (hPSC) technology may generate therapeutic mDA neurons for implantation in patients with PD. Although some initial clinical trial results are promising for this approach, it is likely that dysregulated dopamine release in some patients leads to no symptom improvement or uncontrollable movements.3 The ability to remotely fine-tune dopamine release from implanted mDA neurons is necessary to improve clinical efficacy for this therapeutic strategy.

Chen et al4 have created hPSC-derived mDA neurons that were engineered to express DREADDs (designer receptor exclusively activated by designer drug). Dopamine release is regulated by exogenous administration of an otherwise inert small molecule, the receptor agonist clozapine-N-oxide (CNO), to activate the DREADDs in mDA neurons. With the use of CRISPR (clustered regularly interspaced short palindromic repeats) technology, human embryonic stem cell lines (hESCs) were created with inhibitory (hM4Di) and excitatory DREADDs (hM3Dq) and then differentiated into mDA neurons. By patch-clamping analysis, CNO induced depolarization of excitatory neuron but induced hyperpolarization in inhibitory mDA neurons, suggesting direct CNO regulation of these 2 types of neurons.